| Dissertation |
Thesis (Ph.D.) --NUI, 2012 at Department of Anatomy & Neuroscience, UCC. |
| Summary |
Hippocampal neurogenesis is thought to be impaired in neurodegenerative and psychiatric disorders. Neuroinflammation is also associated with the neuropathology of these disorders due to the inappropriate release of pro-inflammatory cytokines such as interleukin-1β (IL-1β) from activated microglia. Glycogen synthase kinase-3β (GSK-3) and the orphan nuclear receptor TLX are key regulators of hippocampal neurogenesis. GSK-3β negatively regulates Wnt signaling, a vital pathway promoting neurogenesis, and TLX is required to maintain neural precursor cells (NPCs) in an undifferentiated state. In addition to this, GSK-3 has also been shown to positively regulate pro-inflammatory cytokine production in monocytes. The aims of these studies were to assess the effect of an inflammatory environment (IL-1) and GSK-3 inhibition on hippocampal NPC proliferation and differentiation, and to investigate the role of GSK-3 in LPS-induced cytokine production in vitro. We have confirmed a negative role for IL-1 in hippocampal neurogenesis in vitro by demonstrating an anti-proliferative, anti-neurogenic and pro-gliogenic effect of IL-1 on NPCs. We show that these effects are mediated by GSK-3and are paralleled by a decrease in TLX expression, which can be prevented in neurons by GSK-3β inhibition. In addition to this we demonstrate that GSK-3 differentially mediates LPS-induced cytokine production from glial-enriched cultures. This thesis contributes to the growing body of evidence that IL-1 is detrimental to hippocampal neurogenesis. We have identified a two-tier role for GSK-3in CNS inflammationpharmacological inhibition of GSK-3 reduces pro-inflammatory mediators in the CNS while simultaneously promoting neurogenesis. Furthermore, we show that TLX is vulnerable to an inflammatory environment and thus may be a potential target to restore levels of endogenous neurogenesis. This research on the molecular mechanisms involved in inflammation-induced changes in hippocampal neurogenesis provides important insights for the development of appropriate treatments for disorders involving inflammation-induced impaired neurogenesis. |
| Subject |
Anatomy.
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Neurosciences.
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| Collection |
Theses Ph.D.
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Theses Anatomy and Neuroscience Department
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| Description |
283 p. ; 30 cm. |
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